The present invention is directed to tissue irrigating solutions and, more particularly, to an improved technique for formulating and packaging the components of a tissue irrigating solution containing glutathione, bicarbonate, and Ringer solution.
During the surgical procedures, it has been found extremely important to minimize disturbance of the environment of tissue and cells as much as possible. A traumatic change in the environment surrounding internal cells may lead to the destruction of such cells or the destruction of the function of such cells. The destruction of cell function may even lead to destruction of other cells which are dependent upon a proper functioning of the destroyed cells. Therefore, during surgical procedures such as, for example, intraocular surgery, it is very important that the exposed tissue be continuously irrigated with solutions which approximate natural body fluids. Such solutions are called "tissue irrigating solutions". One of the earliest tissue irrigating solutions for ophthalmic procedures was an isotonic saline. However, it was quickly recognized that the isotonic saline was not adequate as an ophthalmic irrigating solution because it resulted in endothelial cell swelling, cell damage, and consequent corneal clouding.
Alternatively, various electrolyte solutions have been proposed as tissue irrigating solutions, particularly in ophthalmic procedures, because such solutions more closely resemble the aqueous humor of the eye. The earliest electrolyte solution was known as Ringer's solution, which was a combination of sodium, calcium and potassium ions along with sodium lactate. Another solution intended for tissue irrigation is known as a balanced salt solution which contains the essential sodium, potassium, calcium, and magnesium salt ions along with an acetate-citrate buffer system. It has been somewhat successful and was used extensively until several years ago. Within the last 10-15 years, there has developed a tissue irrigating solution which is a combination of the Ringer solution along with glutathione and sodium bicarbonate. This is sometimes referred to GBR, and in recent years has become a recognized tissue irrigating solution, especially for ophthalmic procedures. When dextrose, sodium hydrogen phosphate (Na.sub.2 HPO.sub.4), and sometimes adenosine are added to GBR, there results a fortified or enhanced balanced salt solution (sometimes referred to as "BSS Plus), which has proven to be the most effective for intraocular surgery.
The problem with all GBR solutions and particularly the fortified or enhanced balanced salt solution is that they are not stable. Because they must be mixed essentially at the operative site, it is difficult to control and maintain sterility. There are various reasons why GBR type solutions are not stable. First, bicarbonate and phosphate tend to precipitate in the presence of the magnesium and calcium ions. Therefore, once mixed, the sodium bicarbonate quickly loses its ability to act as a pumping agent for causing the endothelium to perform its fluid transport function of maintaining an outward fluid transport to the stromal layer, which results in damage to the cornea. Stated otherwise, the purpose of the bicarbonate is to act as a pump and, when mixed with the magnesium or calcium ions, it quickly loses its propensity for pumping. A second reason why the GBR solutions are not stable is that bicarbonate decomposes at a pH of less than 8 and be-comes carbon dioxide which again causes the bicarbonate to fail to act as a chemical pump during the surgical procedure. Finally, the glutathione is unstable at a pH greater than 5. Therefore, the glutathione cannot exist in a basic solution and the bicarbonate cannot exist for extended periods in an acid solution.
A solution to this problem has been offered in U.S. Pat. Nos. 4,443,432 and 4,550,022, both issued to Garabedian et al. According to these two patents, initially two solutions are prepared, one a basic solution providing the bicarbonate and sodium phosphate, and the second an acidic solution which provides the calcium and magnesium ions, as well as the dextrose and glutathione. The solutions are packaged and stored separately for extended periods of time and mixed within 24 hours of use. While the resulting irrigating product as described the Garabedian et al technique has achieved some degree of acceptance and success, there are some limitations as a result thereof. The long-term stability and maintenance of acceptable pH values is difficult in accordance with the method and technique described in the Garabedian et al patents. In order to steam sterilize the large solution, it is necessary to place the glutathione in the smaller package, because glutathione cannot stand steam sterilizing. Therefore, since the sodium bicarbonate is in the larger package, the large package must be glass, because it is difficult to maintain the stability of sodium bicarbonate in solution in a polymeric container. This occurs because sodium bicarbonate will not remain stable as a result of the transmission of vapors through the wall of the polypropylene bottle.